An indazole-pyrazole skeleton compound and use thereof

Abstract

The present disclosure relates to an indazole-pyrazole skeleton compound and use thereof. Specifically, the present disclosure provides a compound as shown in formula I or a pharmaceutically acceptable salt thereof. The compound of the present disclosure has good inhibitory effect on PDE4 and good therapeutic effect on acute lung injury.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to an indazole-pyrazole skeleton compound and its uses. Background Technology

[0002] Phosphodiesterase 4 (PDE4) belongs to the phosphodiesterase family and is responsible for the degradation of cyclic adenosine monophosphate (cAMP) in vivo. It is the earliest discovered and most abundant protein in the phosphodiesterase family, working with nucleotide cyclases to regulate intracellular cAMP levels and playing a crucial role in cAMP signaling homeostasis. PDE4 contains four isoforms: A, B, C, and D. Isoform C is less commonly expressed in vivo, while isoforms A, B, and D are the most prevalent. Significant expression differences exist among isoforms in different tissues and organs, with isoforms B and D being the most studied. Different splicing variants of each isoform result in various splicing variants, which can be classified into long, short, ultra-short, and dead-short forms based on differences in upstream conserved regions (UCRs). Among them, the long PDE4 includes UCR1 and UCR2, the short type only includes UCR2, and the ultra-short type includes truncated UCR2. Each PDE4 subtype and splice variant may have its own unique function.

[0003] cAMP is a crucial signaling molecule that regulates important physiological and pathological processes such as inflammatory responses, fibrosis, bodily injury, and central nervous system function. It can influence the occurrence and development of inflammation, the formation of fibrosis, post-injury inflammation and repair processes, neurogenesis, the establishment of neuronal circuits, apoptosis, neuronal plasticity, sleep, sensorimotor gating, emotional stability, memory, and other cognitive functions. PDE4, as a key member regulating cAMP signaling, has received considerable attention in recent years for its application in the treatment of diseases related to inflammation, fibrosis, injury, and the central nervous system. Related diseases include inflammatory diseases such as chronic obstructive pulmonary disease (COPD), asthma, dermatitis, hepatitis, non-alcoholic fatty liver disease (NAFLD), psoriasis, rhinitis, Behçet's syndrome, arthritis, eczema, vitiligo, and ulcerative colitis; fibrotic diseases such as pulmonary fibrosis, liver fibrosis, and cystic fibrosis; injury-related diseases such as lung injury, liver injury, kidney injury, edema, and traumatic brain injury; and central nervous system diseases such as Alzheimer's disease, depression, anxiety, multiple sclerosis, stroke, and cognitive improvement.

[0004] PDE4 participates in various physiological functions and is closely related to a variety of diseases by regulating cAMP levels in the body. The main pathways in which PDE4 is involved include the cAMP / PKA / CREB signaling pathway and the MAPK / ERK / CREB pathway. By inhibiting PDE4 activity, cAMP hydrolysis is blocked, and the cellular level increases, which in turn activates cAMP-dependent protein kinase A (PKA), activating the cAMP / PKA / CREB and / or MAPK / ERK / CREB signaling pathways. This, in turn, regulates the expression of multiple target genes, including BDNF, Bax, PEPCK, and IL-2, thereby participating in a variety of physiological and pathological processes related to inflammation, fibrosis, injury, memory, and learning.

[0005] Numerous clinical and preclinical studies have demonstrated that regulating PDE4 activity and cAMP levels through inhibitors can treat a variety of diseases. Several PDE4 inhibitors are currently on the market, including roflumilast, apremilast, and claborone. Due to gastrointestinal and central nervous system side effects of marketed drugs, PDE4 inhibitors remain a hot research topic. Improving the therapeutic index is the primary research goal, with key research directions including altering the route of administration, discovering highly active subtype-selective inhibitors, dual-target inhibitors, discovering inhibitors that have difficulty crossing the blood-brain barrier, and investigating indications.

[0006] The above studies indicate that PDE4 is a promising druggable target with great therapeutic potential in inflammatory diseases, fibrosis-related diseases, injury-related diseases, and central nervous system-related diseases. There is an urgent need to develop novel PDE4 inhibitors for the development of candidate drugs for these diseases. Summary of the Invention

[0007] A compound as shown in Formula I, or a pharmaceutically acceptable salt thereof.

[0008]

[0009] Where Z is

[0010] X is O or NR 5 ;

[0011] R 1 and R 5 Each is independently hydrogen, unsubstituted or R 1-1 Replacement C 1-6 alkyl;

[0012] R 2 Hydrogen, unsubstituted or R 2-1 Replacement C 1-6 Alkyl, unsubstituted or R 2-2Substituted 3-6 membered cycloalkyl, unsubstituted or R 2-3 Substituted 3-6 membered heterocyclic alkyl groups;

[0013] R 3 and R 4 Each can be independently represented by hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, or C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0014] R 1-1 and R 2-1 Each can be independently a halogen, hydroxyl, mercapto, amino, nitro, cyano, or C group. 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0015] R 2-2 and R 2-3 Each can be independently a halogen, hydroxyl, mercapto, amino, nitro, cyano, or C group. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 carboxyl;

[0016] R 5 and R 6 Each can be independently a halogen, hydroxyl, mercapto, amino, nitro, cyano, or C group. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0017] n1 is 0, 1, 2 or 3;

[0018] n2 can be 0, 1, 2, 3 or 4.

[0019] In some embodiments, X is O in the compound of Formula I or a pharmaceutically acceptable salt thereof;

[0020] R 1 Hydrogen, unsubstituted or R 1-1 Replacement C 1-6 alkyl;

[0021] R 2 Hydrogen, unsubstituted or R 2-1 Replacement C 1-6 alkyl;

[0022] R 3 and R 4Each can be independently represented by hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, or C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy;

[0023] R 1-1 and R 2-1 Each can be independently halogenated, hydroxyl, amino, nitro, or cyano.

[0024] R 2-2 and R 2-3 Each is independently a halogen, hydroxyl, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyl group.

[0025] In some implementations, X is O.

[0026] In some implementation schemes, R 1 Hydrogen, unsubstituted or R 1-1 Replacement C 1-6 alkyl.

[0027] In some implementation schemes, R 1 For not replaced or by R 1-1 Replacement C 1-6 alkyl.

[0028] In some implementation schemes, R 1 It can be hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0029] In some implementation schemes, R 1 The derivatives are hydrogen, methyl, ethyl, n-propyl, and isopropyl.

[0030] In some implementation schemes, R 1 It is an ethyl group.

[0031] In some implementation schemes, R 2 Hydrogen, unsubstituted or R 2-1 Replacement C 1-6 alkyl.

[0032] In some implementation schemes, R 2 It can be hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0033] In some implementation schemes, R 2 The derivatives are hydrogen, methyl, ethyl, n-propyl, and isopropyl.

[0034] In some implementation schemes, R 2 It is hydrogen.

[0035] In some implementation schemes, R 3 and R 4 Each is independently hydrogen, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyl group.

[0036] In some implementation schemes, R 3 and R 4 Each is independently hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyl group.

[0037] In some implementation schemes, R 3 and R 4 It is hydrogen.

[0038] In some implementation schemes, R 1-1 and R 2-1 Each can be independently classified as halogen, hydroxyl, amino, nitro, or cyano.

[0039] In some implementation schemes, R 2-2 and R 2-3 Each is independently a halogen, hydroxyl, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyl group.

[0040] In some implementations, n1 is 0.

[0041] In some implementations, n2 is 0.

[0042] In some implementation schemes, R 1 R 2 and R 5 In, the C 1-6 Each alkyl group is independently C10. 1-4 Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0043] In some implementation schemes, R 2 In this context, each of the 3-6 membered cycloalkyl groups is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0044] In some implementation schemes, R 2 In this context, each of the 3-6 membered heterocyclic alkyl groups is independently a 3-6 membered heterocyclic alkyl group whose heteroatoms are selected from one or more of N, O and S, and whose number of heteroatoms is 1, 2 or 3.

[0045] In some implementation schemes, R 3 R 4 R 1-1 R 2-1 R 2-2 R 2-3 R 5 and R 6 In this context, each of the halogens is independently fluorine, chlorine, or bromine.

[0046] In some implementation schemes, R 3 R 4 R 2-2 R 2-3 R 5 and R 6 In, the C 1-4 Each alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0047] In some implementation schemes, R 3 R 4 R 1-1 R 2-1 R 2-2 R 2-3 R 5 and R 6 In, the C 1-4 The alkyl group in the haloalkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0048] In some implementation schemes, R 3 R 4 R 1-1 R 2-1 R 2-2 R 2-3 R 5 and R 6 In, the C 1-4 The halogen in the haloalkyl group is independently fluorine, chlorine, or bromine. In some embodiments, R 3 R 4 R 1-1 R 2-1 R 2-2 and R 2-3 In, the C 1-4 The halogens in haloalkyl groups are each independently fluorine.

[0049] In some implementation schemes, R 3 R 4 R 1-1 R 2-1 R 2-2 R 2-3R 5 and R 6 In, the C 1-4 The alkyl group in the haloalkyl group is independently -CF3, -CHF2 or -CH2F.

[0050] In some implementation schemes, R 3 R 4 R 1-1 R 2-1 R 2-2 R 2-3 R 5 and R 6 In, the C 1-4 Each alkoxy group is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0051] In some implementation schemes, R 3 R 4 R 1-1 R 2-1 R 2-2 R 2-3 R 5 and R 6 In, the C 1-4 The alkoxy groups in the haloalkoxy groups are each independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0052] In some implementation schemes, R 3 R 4 R 1-1 R 2-1 R 2-2 R 2-3 R 5 and R 6 In, the C 1-4 The halogen in a haloalkoxy group is fluorine, chlorine, or bromine, each independently.

[0053] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof has any of the following structures:

[0054]

[0055]

[0056] This disclosure provides a pharmaceutical composition comprising the compound shown in Formula I above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0057] This disclosure also provides the use of the above-described compound of Formula I or a pharmaceutically acceptable salt thereof or the above-described pharmaceutical composition in the preparation of a medicament as a PDE4 inhibitor. In some embodiments, the PDE4 inhibitor is a PDE4B and / or a PDE4D inhibitor.

[0058] This disclosure also provides the use of the above-described compound of Formula I or a pharmaceutically acceptable salt thereof or the above-described pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of PDE4-related diseases. In some embodiments, the PDE4 is PDE4B and / or PDE4D. In some embodiments, the PDE4-related diseases are inflammatory diseases, fibrotic diseases, traumatic diseases, and central nervous system diseases. In some embodiments, the inflammatory diseases include chronic obstructive pulmonary disease, asthma, dermatitis, hepatitis, non-alcoholic fatty liver disease, psoriasis, rhinitis, Behçet's syndrome, arthritis, eczema, vitiligo, and ulcerative colitis. In some embodiments, the fibrotic diseases include pulmonary fibrosis, liver fibrosis, and cystic fibrosis. In some embodiments, the traumatic diseases include lung injury, liver injury, kidney injury, edema, and traumatic brain injury. In some embodiments, the central nervous system diseases include Alzheimer's disease, antidepressants, anti-anxiety medications, multiple sclerosis, stroke, and cognitive impairment-related diseases. In some embodiments, the PDE4-related disease is acute lung injury.

[0059] This disclosure also provides the use of the above-described compound of Formula I or a pharmaceutically acceptable salt thereof or the above-described pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of diseases, said diseases being inflammatory diseases, fibrotic diseases, traumatic diseases, and central nervous system diseases. In some embodiments, the inflammatory diseases include chronic obstructive pulmonary disease, asthma, dermatitis, hepatitis, non-alcoholic fatty liver disease, psoriasis, rhinitis, Behçet's syndrome, arthritis, eczema, vitiligo, and ulcerative colitis. In some embodiments, the fibrotic diseases include pulmonary fibrosis, liver fibrosis, and cystic fibrosis. In some embodiments, the traumatic diseases include lung injury, liver injury, kidney injury, edema, and traumatic brain injury. In some embodiments, the central nervous system diseases include Alzheimer's disease, antidepressants, anti-anxiety medications, multiple sclerosis, stroke, and cognitive improvement. In some embodiments, the disease is acute lung injury.

[0060] This disclosure also provides a compound as shown in Formula II or a pharmaceutically acceptable salt thereof.

[0061]

[0062] Where Y is a nitro or amino group; Z and R 5 n1 is defined by any scheme of the compound shown in Formula I.

[0063] In some embodiments, the compound shown in Formula II has any of the following structures:

[0064]

[0065]

[0066] This disclosure also provides a method for preparing a compound as shown in Formula I, comprising the following steps:

[0067] (1) The compound shown in Formula IV reacts with the compound shown in Formula V to give the compound shown in Formula II-1.

[0068] (2) The compound shown in Formula II-1 is reduced to give the compound shown in Formula II-2;

[0069] (3) The compound shown in Formula II-2 reacts with the compound shown in Formula III to obtain the compound shown in Formula I;

[0070]

[0071] Among them, A1 and A2 are halogens independently; Z and R 2 R 5 R 6 n1 and n2 are defined as in any scheme of the compound shown in Formula I.

[0072] Terminology Definition

[0073] Where no specific configuration is defined in this disclosure, the compounds disclosed herein may exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure.

[0074] The compounds and intermediates disclosed herein may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine, lactam-lactamimide isomerization. Examples of lactam-lactamimide equilibria are between A and B as shown below.

[0075]

[0076] All compounds in this disclosure can be classified as type A or type B. All tautomers are within the scope of this disclosure. The nomenclature of compounds does not exclude any tautomers.

[0077] The compounds disclosed herein may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0078] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound disclosed herein, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide a pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0079] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 30 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 10 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and even more preferably an alkyl group containing 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc.

[0080] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.; polycyclic cycloalkyls include spirocyclic, fused-ring, and bridged-ring cycloalkyls.

[0081] The term "heterocyclic alkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, C (=O), or S (=O). m (where m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocyclic alkyl groups include pyrrolidinyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic alkyl groups include spirocyclic, fused-ring, and bridged-ring heterocyclic alkyl groups. Non-limiting examples of "heterocyclic alkyl" include:

[0082]

[0083] etc.

[0084] The heterocyclic alkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocyclic alkyl ring, and non-limiting examples include:

[0085] wait.

[0086] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described above.

[0087] The term "hydroxyl group" refers to -OH.

[0088] The term "thiol" refers to -SH.

[0089] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0090] The term "halogenated alkyl" refers to an alkyl group that has been substituted with a halogen, wherein the alkyl group is as defined above.

[0091] The term "cyano" refers to -CN.

[0092] The term "nitro" refers to -NO2.

[0093] The term "amino" refers to -NH2.

[0094] The term "carboxyl group" refers to -C(O)OH.

[0095] The term "substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine possible or impossible substitutions without much effort (through experiment or theory).

[0096] "Being replaced by one or more..." means that it can be replaced by a single or multiple substituents. When replaced by multiple substituents, it can be a plurality of identical substituents or a combination of one or a plurality of different substituents.

[0097] The term "connection," when referring to the link between two molecules, means that the two molecules are connected by a covalent bond or by a non-covalent bond (e.g., a hydrogen bond or an ionic bond), including direct and indirect connections.

[0098] The term "direct link" refers to the connection between a first compound or group and a second compound or group without any intercalating atoms or groups. The term "indirect link" refers to the connection between a first compound or group and a second compound or group via an intermediate group, compound, or molecule (e.g., a linking group).

[0099] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. Although all the above structural formulas are shown in certain isomer forms for simplicity, this disclosure can include all isomers, such as tautomers, rotatimers, geometric isomers, diastereomers, racemates, and enantiomers. In the chemical structure of the compounds described in this disclosure, the bonds... No configuration was specified, i.e., key The configuration can be E-type or Z-type, or it can contain both E-type and Z-type configurations.

[0100] Unless otherwise specified, the symbols used in this article are as follows: This indicates that it can be connected with one or more groups according to the scope of disclosure described herein.

[0101] In this disclosure, the terms “comprising” or “including” may be replaced with “consisting of”.

[0102] The term "composition" refers to a mixture of a drug containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of the composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0103] The terms “pharmaceutical-grade excipient” or “pharmaceutical-acceptable excipient” include, but are not limited to, any adjuvant, carrier, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0104] Unless otherwise specified, the "compounds" disclosed herein may exist independently as salts, mixed salts, or non-salts (e.g., free acids or free bases). When present as salts or mixed salts, they may be pharmaceutically acceptable or medicinally usable salts.

[0105] The terms “pharmaceutically acceptable salt” and “medicinal salt” are used interchangeably to refer to both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0106] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects and can be prepared by methods known in the art.

[0107] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects, and these salts can be prepared by methods known in the art.

[0108] "Effective amount," "effective dose," "effective therapeutic amount," or "therapeutic effective amount" means the amount of a drug, compound, or pharmaceutical composition necessary to achieve any one or more beneficial or desired therapeutic outcome. For preventative use, beneficial or desired outcomes include eliminating or reducing risk, mitigating severity, or delaying the onset of a condition, including the condition itself, its complications, and the biochemical, histological, and / or behavioral symptoms of intermediate pathological phenotypes that occur during the development of the condition.

[0109] As used herein, the terms “subject,” “patient,” “subject,” or “individual” are used interchangeably and include human or non-human animals, such as mammals, such as humans or monkeys. Attached Figure Description

[0110] Figure 1 Results show the in vitro cellular level anti-inflammatory activity of the compound.

[0111] Figure 2 The results of lung tissue sections from an efficacy test of the compound in acute lung injury.

[0112] Figure 3The results of the efficacy assay for acute lung injury of the compound include: (a) lung dry-wet weight ratio; (b) neutrophil count in lavage fluid; (c) MPO assay; (d) NO assay; (e) TNF-α content in lavage fluid; (f) IL-1β content in lavage fluid; and (g) IL-6 content in lavage fluid. Detailed Implementation Plan

[0113] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the disclosure. Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose source is not specified can be obtained from any supplier of molecular biology reagents at the quality / purity required for molecular biology applications.

[0114] Unless otherwise specified, all reagents used in the following examples are commercially available products.

[0115] Example 1

[0116] Step 1. 3-Bromo-1-(2,2-difluoroethyl)-5-nitro-1H-indazole

[0117]

[0118] The starting material 3-bromo-5-nitroinazole (3.00 g, 12.40 mmol, 1.00 eq) was placed in a 100 mL round-bottom flask, and anhydrous acetonitrile (10 mL) was used as the solvent. Then, 1,1-difluoro-2-iodoethane (1637 μl, 18.60 mmol, 1.50 eq) and potassium carbonate (571 mg, 4.14 mmol, 2.00 eq) were added sequentially, and the mixture was heated to reflux at 85 °C for 12 h. After the reaction was detected by TLC, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the organic phase was evaporated to dryness under reduced pressure. The solution was redissolved in ethyl acetate, and water was added. The solution was extracted three times with ethyl acetate (20 mL × 3). The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate for 0.5 h, and the solvent was removed under reduced pressure. The solution was then purified by column chromatography (petroleum ether: dichloromethane = 8:1) using a wet column chromatography method to obtain 2.99 g of a pale yellow solid powder, with a yield of 79%.

[0119] 1 HNMR(300MHz,DMSO-d6)δ8.50(d,J=1.6Hz,1H),8.37(dd,J=9.3,2.2Hz,1H),8.02 (d,J=9.7Hz,1H),6.49(tt,J=54.3,3.3Hz,1H),5.09(td,J=15.5,3.3Hz,2H)ppm.

[0120] Step 2. Preparation of 1-(2,2-difluoroethyl)-3-(1-ethyl-1H-pyrazol-5-yl)-5-nitro-1H-indazole

[0121]

[0122] The intermediate (380 mg, 1.25 mmol, 1.00 eq) and 1-ethylpyrazole-5-boronic acid (456 mg, 3.26 mmol, 2.00 eq) were placed in a 50 mL two-necked flask and dissolved in a mixed solvent of toluene (8 mL) and methanol (4 mL). Then, 2 mL of sodium carbonate (532 mg, 5.02 mmol, 4.00 eq) aqueous solution was added. After vacuuming for 5 min, the catalyst [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (92 mg, 0.13 mmol, 0.1 eq) was added, and vacuuming was continued for 10 min. The mixture was then heated to reflux at 100 °C for 14 h under nitrogen protection. After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature, filtered with diatomaceous earth, the organic solvent was removed by vacuum evaporation, an appropriate amount of water was added, and the solution was extracted three times with ethyl acetate (30 mL × 3). The organic phases were collected and combined, washed twice with saturated brine, dried over anhydrous sodium sulfate for 0.5 h, concentrated under reduced pressure, and then purified by column chromatography (petroleum ether: ethyl acetate = 32: 1) to obtain 210 mg of a pale yellow solid powder product, with a yield of 40%.

[0123] 1 HNMR (300MHz, DMSO-d6) δ8.74(d,J=1.5Hz,1H),8.38(dd,J=9.3,2.1Hz,1H),8.06(d,J=9.3Hz,1H),7.68(d,J=2.0Hz,1H),7.05 (d,J=2.0Hz,1H),6.56(tt,J=54.3,3.2Hz,1H),5.17(td,J=15.6,3.2Hz,2H),4.52(q,J=7.1Hz,2H),1.35(t,J=7.1Hz,3H)ppm.

[0124] Step 3. Preparation of 1-(2,2-difluoroethyl)-3-(1-ethyl-1H-pyrazol-5-yl)-1H-indazole-5-amine

[0125]

[0126] The intermediate (270 mg, 0.79 mmol, 1.00 eq) was placed in a 50 mL single-necked flask and dissolved in a mixed solvent of ethanol (12 mL) and water (6 mL). Then, iron powder (177 mg, 3.17 mmol, 4.00 eq) and ammonium chloride (423 mg, 7.92 mmol, 10.00 eq) were added sequentially, and the mixture was heated to reflux at 80 °C for 4 h. After the reaction was completed by TLC, the mixture was filtered while hot. The filtrate was added with an appropriate amount of water and extracted three times with dichloromethane (30 mL × 3). The organic phases were combined and washed twice with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate for 0.5 h and concentrated under reduced pressure to obtain 170 mg of a reddish-brown flaky solid product, with a yield of 89%.

[0127] 1 HNMR(300MHz,DMSO-d6)δ7.59(d,J=1.9Hz,1H),7.52(d,J=9.5Hz,1H),7.00–6.86(m,2H),6.66(d,J=1.9Hz,1H),6.44 (tt,J=54.8,3.6Hz,1H),5.29(s,2H),4.89(td,J=15.2,3.6Hz,2H),4.50(q,J=7.1Hz,2H),1.33(t,J=7.1Hz,3H)ppm.

[0128] Step 4. Preparation of ethyl acetate (4-((1-(2,2-difluoroethyl)-3-(1-ethyl-1H-pyrazol-5-yl)-1H-imidazol-5-yl)amino)phenyl) (Compound 2)

[0129]

[0130] The intermediate (210 mg, 0.68 mmol, 1.00 eq) and methyl p-bromophenylacetate (118 μl, 0.75 mmol, 1.10 eq) were placed in a 25 mL two-necked flask and dissolved in anhydrous toluene (6 mL). Cesium carbonate (440 mg, 1.35 mmol, 2.00 eq) and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (84 mg, 0.135 mmol, 0.20 eq) were added sequentially. After vacuuming for 5 min, palladium acetate (15 mg, 0.068 mmol, 0.10 eq) was added, and vacuuming was continued for 10 min. The mixture was then heated to reflux at 100 °C for 20 h under nitrogen protection. After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature, filtered with diatomaceous earth, the organic solvent was removed by vacuum evaporation, an appropriate amount of water was added, and the solution was extracted three times with ethyl acetate (30 mL × 3). The organic phases were collected and combined, washed twice with saturated brine, dried with anhydrous sodium sulfate for 0.5 h, concentrated under reduced pressure, and then purified by column chromatography (petroleum ether: ethyl acetate = 16:1) to obtain 85 mg of yellow solid powder product, with a yield of 49%.

[0131] MP150-153℃. 1 HNMR(300MHz,DMSO-d6)δ8.19(s,1H),7.74(d,J=9.0

[0132] Hz,1H),7.60(d,J=1.9Hz,1H),7.43(d,J=1.9Hz,1H),7.31(dd,J=9.0,2.0Hz,1H),7.11(d,J=8.5Hz,2H),7.01(d,J=8.6Hz,2H),6.69(d,J =1.9Hz,1H),6.68–6.30(m,1H),4.98(td,J=15.3,3.5Hz,2H),4.50(q,J=7.1Hz,2H),3.60(s,3H),3.56(s,2H),1.35(t,J=7.1Hz,3H)ppm. 13 C NMR (101MHz, CDCl3) δ172.51,143.35,138.75,137.89,137.82,135.97,133.45,130.35,125.89,123.74,122.94,116 .61,116.30,113.87,111.44,110.12,109.04,106.37,52.07,51.33(t,J=28.3Hz),45.99,40.40,15.72ppm.HRMS(ESI + ):m / z[M+H + Calculated for C 23H 23 F2N5O2,440.1898; found440.1891.HPLC purity=95.02%,t R = 14.44 min.

[0133] Step 5. Preparation of 2-(4-((1-(2,2-difluoroethyl)-3-(1-ethyl-1H-pyrazol-5-yl)-1H-imidazol-5-yl)aminophenyl)acetic acid (compound 1)

[0134]

[0135] Compound 2 (95 mg, 0.21 mmol, 1.00 eq) was dissolved in 3 mL of methanol, and then 2 mL of KOH (33 mg, 0.83 mmol, 4.00 eq) aqueous solution was added. The mixture was heated to reflux at 80 °C for 4 h. After the reaction was completed by TLC, the solvent was removed by vacuum distillation. After adding an appropriate amount of water, the pH was adjusted to 1-2 with dilute hydrochloric acid (1 mol / L) solution. The mixture was then extracted three times with ethyl acetate (20 mL × 3). The organic phases were collected and combined, dried over anhydrous sodium sulfate for 0.5 h, concentrated under reduced pressure, and then purified by column chromatography (dichloromethane:methanol = 80:1) to give 22 mg of a pale yellow powder solid product, with a yield of 54%.

[0136] MP139-140℃. 1 H NMR (300MHz, DMSO-d6) δ11.70 (s, 1H), 8.16 (d, J = 5.9

[0137] Hz,1H),7.73(d,J=9.0Hz,1H),7.59(s,1H),7.43(s,1H),7.30(d,J=9.1Hz,1H),7.20–7.05(m,2H),7.01(d,J=8.3Hz,2H),6.68(d,J= 6.6Hz,1H),6.49(tt,J=54.6,3.6Hz,1H),4.98(td,J=15.2,3.4Hz,2H),4.50(q,J=7.1Hz,2H),3.45(s,2H),1.35(t,J=7.0Hz,3H)ppm. 13C NMR (101MHz, DMSO) δ173.68,143.30,139.04,138.91,137.53,134.65,133.70,130.66,126.28,123.06,122.03,1 17.65,117.29,116.35,114.89,112.49,111.74,106.14,105.30,50.71(t,J=25.3Hz),45.75,16.11ppm.HRMS(ESI + ):m / z[M+H + calculated for C 22 H 21 F2N5O2,426.17416; found 426.17300.HPLC purity=98.07%,t R = 8.31 min.

[0138] Test Example 1: PDE4 Inhibitory Activity Test

[0139] The specific testing method is as follows:

[0140] Preparation of compound solutions:

[0141] By calculation, 0.005 mmol of each test compound was accurately weighed, dissolved in 0.5 mL of DMSO, and mixed thoroughly by repeated blowing and blowing to prepare a 10 mM stock solution. The stock solution was then serially diluted to ten concentrations: 1 mM, 100 μM, 10 μM, 1 μM, 100 nM, 10 nM, 1 nM, 0.1 nM, and 0.01 nM.

[0142] Preparation of mixed solutions:

[0143] (1) PDE4B1 stock solution (10 nM): Take 10 μg of enzyme (MW = 109 kDa, purity 70%), dissolve it in 6.419 mL of buffer (25 mM Tris-HCl, pH 8.0, 100 mM sodium chloride, 0.05% Tween-20, 50% glycerol and 3 mM DTT), slowly pipette to mix well, and divide into 10 tubes, 641.9 μL / tube. Before use, reconstitute on ice for 5 min, then at room temperature for 3 min, slowly pipette to mix well, and slowly pipette 3 times before sampling.

[0144] (2) Buffer solution: an aqueous solution containing 61 mM Tris-HCl, 12 mM MgCl2, 61 mM KCl, 6.1 mM TCEP, 0.48 mM PEP, 0.012 mM NADH and 0.048 mM ATP, pH 8.0, prepared in 60 mL.

[0145] (3) Myokinase solution: Take the enzyme suspension stored at 2-8℃, let it stand at room temperature for 5 minutes, and slowly beat it to mix it evenly. Accurately measure 65μL of enzyme suspension, add 335μL of buffer to prepare a 335μL solution, and slowly blow it to mix it evenly (store on ice).

[0146] (4) Pyruvate kinase solution: Take 0.3 mg of enzyme solid powder stored at -80℃, dissolve it in 200 μL buffer, and slowly pipette to mix it evenly (store on ice).

[0147] (5) Lactate dehydrogenase solution: Take 0.9 mg of enzyme solid powder stored at -80℃, dissolve it in 200 μL buffer, and slowly blow it to mix it evenly (store on ice).

[0148] (6) PDE4B1 solution: Take the aliquoted solution stored at -80℃, reconstitute on ice for 5 min, reconstitute at room temperature for 5 min, and gently blow and mix before use.

[0149] (7) cAMP solution (0.032mM): Take an appropriate amount of cAMP and prepare 2 mL of 0.032mM solution with buffer.

[0150] Operating procedures:

[0151] (1) Prepare a mixed solution in a 96-well plate. First, add 145 μL of buffer, then add 6 μL of myokinase, 3.2 μL of pyruvate kinase, 2 μL of lactate dehydrogenase, and 10 μL of PDE4B1 solution in sequence. After each addition of solution, slowly pipette 3 times to mix evenly.

[0152] (2) Add 10 μL of the corresponding concentration of compound solution in sequence, slowly blow and mix evenly. Replace the blank group (no compound) with an equal volume of DMSO and incubate at room temperature for 5 to 10 minutes.

[0153] (3) Add 25 μL of cAMP solution before the assay, blow it 3 times to mix it evenly, and replace the cAMP well with an equal volume of buffer.

[0154] (4) Excitation wavelength 355nM, emission wavelength 460nM, continuous measurement for 10 minutes, stop measurement after the plateau appears.

[0155] Data processing: Microsoft Excel 2010 spreadsheet software was used for data processing. The calculation formula is as follows:

[0156] Inhibition%=(Signal-Min) / (Max-Min)*100%

[0157] Signal: NADH fluorescence intensity in the inhibitor pore; Max: NADH fluorescence intensity in the cAMP-free pore; Min: NADH fluorescence intensity in the compound-free pore.

[0158] The results are shown in Table 1:

[0159] Table 1. Inhibitory activity of compounds against PDE4B

[0160]

[0161] Conclusion: Compound 1 exhibits 20 nM inhibitory activity against PDE4B1, which is 450 times that of the positive control drug cyclophosphamide and 10 times that of the self-developed positive control compound, demonstrating excellent in vitro enzyme activity.

[0162] Test Example 2: In vitro cellular level anti-inflammatory activity test of compounds

[0163] Specific testing method: The effect of PDE4B inhibitors on the production of the inflammatory cytokine TNF-α was detected by ELISA. The cell density was adjusted to 2×10⁶ cells / year. 5 Cells were seeded at a rate of 100 μL / mL in 96-well plates and incubated at 37°C with 5% CO2 saturated humidity for 12 h until cell adhesion. The experiment consisted of a blank control group, an LPS control group, and an experimental group. Different concentrations of the test compound (10 μM, 25 μM, and 50 μM) were added to each well of the experimental group, and the plates were incubated for 1 h. Except for the blank control group, each group was incubated with LPS solution (200 ng / mL) for 24 h. The culture medium from each well was then transferred to centrifuge tubes and centrifuged at 3500 rpm for 10 min at 4°C. The supernatant was used to determine the level of TNF-α.

[0164] The results are as follows Figure 1 As shown, RAW 264.7 cells were induced with LPS, and the inflammatory factor TNF-α compound 1 inhibited the inflammatory response of cells in a dose-dependent manner at 1 μM, 2 μM, and 4 μM, demonstrating good anti-inflammatory activity.

[0165] Test Example 3: Results of Lung Tissue Sections in Acute Lung Injury Efficacy Test of Compound

[0166] Specific testing methods: First, an acute lung injury model in mice was established using LPS-induced induction. Mice were anesthetized (1.25% aphthylamine, 0.2 mL / kg, intraperitoneal injection), and the trachea was exposed. 60 μL of lipopolysaccharide solution was instilled into the trachea using a 1 mL syringe. After injection, the mice were upright and rotated 30 times, then left upright for 2-3 minutes. The neck was sutured, and the mice were placed in a suitable temperature environment until they recovered. They were then returned to their cages for continued rearing. The model was successfully established. Lung tissue was isolated, preserved in formalin solution, stained with hematoxylin and eosin (HE), and lung tissue sections were observed under a microscope. The results were reported.

[0167] The results are as follows Figure 2 As shown, the model group showed more severe congestion compared to the control group, with a greater number of red blood cells. Most alveolar cavities were filled with pink fluid (edema fluid) and a small number of red blood cells, with a few gas vacuoles also visible. The positive control group and the low-dose compound 1 group showed significantly less congestion, fewer red blood cells that were concentrated only in certain areas, and narrow, elongated gas vacuoles. The high-dose compound 1 group showed less cellular congestion, fewer red blood cells, less obvious areas of red blood cell aggregation, and smaller gas vacuoles.

[0168] Test Example 4: Results of Pharmacodynamic Indicators in Acute Lung Injury Pharmacodynamic Test of Compounds

[0169] Specific testing methods: The establishment of the LPS-induced acute lung injury model in mice was the same as in test case 3. The collection method for bronchoalveolar lavage fluid (BALF) was as follows: Mice were euthanized after blood collection by enucleation, fixed on the operating table, and dissected. The right lung was ligated, and an endotracheal tube was inserted and fixed using an indwelling intravenous catheter. The left bronchus was then lavaged with 0.3 mL of PBS (1×) solution, repeated three times. The recovered bronchoalveolar lavage fluid was mixed, centrifuged at 4°C for 10 min, and the supernatant was stored at -80°C. The levels of inflammatory factors TNF-α, IL-1β, and IL-6 in BALF were measured using an ELISA kit. Mice were dissected, lung tissue was collected, homogenized, and the MPO and NO activities in the lung tissue were tested according to the kit instructions.

[0170] The results are as follows Figure 3 As shown, both low and high doses of compound 1 were superior to the positive control drug dexamethasone in inhibiting neutrophils and restoring MPO activity and NO levels. In inhibiting inflammatory factors TNF-α, IL-1β, and IL-6, the low dose of WPBL-II-06 was roughly equivalent to the positive control drug, while the high dose was better. Furthermore, the analysis showed that all indicators exhibited a clear dose-dependent effect. Therefore, there is reason to believe that compound 1 has significant potential in treating lung inflammation, particularly acute lung injury or acute respiratory distress syndrome.

Claims

1. A compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, in, Z is X is O or NR 5 ; R 1 and R 5 Each is independently hydrogen, unsubstituted, or R-substituted. 1-1 Replacement C 1-6 alkyl; R 2 Hydrogen, unsubstituted or R 2-1 Replacement C 1-6 Alkyl, unsubstituted or R 2-2 Substituted 3-6 membered cycloalkyl, unsubstituted or R 2-3 Substituted 3-6 membered heterocyclic alkyl groups; R 3 and R 4 Each can be independently represented by hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, or C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups; R 1-1 and R 2-1 Each can be independently a halogen, hydroxyl, mercapto, amino, nitro, cyano, or C group. 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Carboxyl group, -C(=O)-C 1-4 Alkyl group, -NHC(=O)-C 1-4 Alkyl or -C(=O)NH-C 1-4 alkyl; R 2-2 and R 2-3 Each can be independently a halogen, hydroxyl, mercapto, amino, nitro, cyano, or C group. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 carboxyl; R 5 and R 6 Each can be independently a halogen, hydroxyl, mercapto, amino, nitro, cyano, or C group. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups; n1 is 0, 1, 2 or 3; n2 can be 0, 1, 2, 3 or 4.

2. The compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, In the compound or its pharmaceutically acceptable salt as shown in Formula I, X is O; R 1 Hydrogen, unsubstituted or R 1-1 Replacement C 1-6 alkyl; R 2 Hydrogen, unsubstituted or R 2-1 Replacement C 1-6 alkyl; R 3 and R 4 Each can be independently represented by hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, or C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy; R 1-1 and R 2-1 Each can be independently halogenated, hydroxyl, amino, nitro, or cyano. R 2-2 and R 2-3 Each is independently a halogen, hydroxyl, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyl group.

3. The compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, R 1 R 2 and R 5 In, the C 1-6 Each alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; And / or, R 2 In this context, each of the 3-6 membered cycloalkyl groups is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; And / or, R 2 In this context, each of the 3-6 membered heterocyclic alkyl groups is independently a 3-6 membered heterocyclic alkyl group whose heteroatoms are selected from one or more of N, O and S, and whose number of heteroatoms is 1, 2 or 3. And / or, R 3 R 4 R 1-1 R 2-1 R 2-2 R 2-3 R 5 and R 6 In this context, each of the halogens is independently fluorine, chlorine, or bromine; And / or, R 3 R 4 R 2-2 R 2-3 R 5 and R 6 In, the C 1-4 Each alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; And / or, R 3 R 4 R 1-1 R 2-1 R 2-2 R 2-3 R 5 and R 6 In, the C 1-4 The alkyl group in the haloalkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; And / or, R 3 R 4 R 1-1 R 2-1 R 2-2 R 2-3 R 5 and R 6 In, the C 1-4 The halogens in the haloalkyl group are each independently fluorine, chlorine, or bromine; And / or, R 3 R 4 R 1-1 R 2-1 R 2-2 R 2-3 R 5 and R 6 In, the C 1-4 Each alkoxy group is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy. And / or, R 3 R 4 R 1-1 R 2-1 R 2-2 R 2-3 R 5 and R 6 In, the C 1-4 The alkoxy groups in the haloalkoxy groups are each independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; And / or, R 3 R 4 R 1-1 R 2-1 R 2-2 R 2-3 R 5 and R 6 In, the C 1-4 The halogen in a haloalkoxy group is fluorine, chlorine, or bromine, each independently.

4. The compound of formula I according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein, The compound shown in Formula I has any of the following structures.

5. A pharmaceutical composition comprising the compound of formula I as described in any one of claims 1-4 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

6. Use of any compound of Formula I as described in any one of claims 1-4, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 5, in the preparation of a medicament as a PDE4 inhibitor.

7. Use of any compound of Formula I according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5, in the preparation of a medicament for the prevention and / or treatment of PDE4-related diseases, wherein the PDE4-related diseases are inflammatory diseases, traumatic diseases, and the traumatic diseases are lung injuries.

8. The use according to claim 7, wherein the PDE4-related disease is acute lung injury.

9. Use of any compound of Formula I according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5, in the preparation of a medicament for the prevention and / or treatment of a disease, said disease being an inflammatory disease, an injury disease, or said injury disease being lung injury.

10. The use according to claim 9, wherein the disease is acute lung injury.

11. A compound as shown in Formula II or a pharmaceutically acceptable salt thereof, in, Y is either nitro or amino; Z, R 5 and n1 as defined in any one of claims 1-4.

12. A method for preparing a compound as shown in Formula I, comprising the following steps: (1) The compound shown in Formula IV reacts with the compound shown in Formula V to give the compound shown in Formula II-1. (2) The compound shown in Formula II-1 is reduced to give the compound shown in Formula II-2; (3) The compound shown in Formula II-2 reacts with the compound shown in Formula III to obtain the compound shown in Formula I; Among them, A1 and A2 are halogens independently; Z and R 2 R 5 R 6 n1 and n2 are as defined in any one of claims 1-4.

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